From: sbharris@ix.netcom.com(Steven B. Harris)
Subject: Re: Grapefruit Juice and Medications
Date: Wed, 03 Dec 1997
Newsgroups: sci.chem,sci.med,sci.bio.misc

In <3484ABBD.E63DD094@netcom.ca> couchac@netcom.ca writes:

>I am searching for any information that is available on the
>complications that grapefruit has on the body's uptake of certain
>medications, including Plendil and Seldane.  I have found that the name
>of the enzyme which is grapefruit specific and not found in any other
>citrus fruit is called a furanocoumarin. If anyone can help me or has
>heard anything concerning this subject, please contact me via email as
>soon as possible.  Thank You
>
>- Mike Couch
>couchac@netcom.ca
>Ontario, Canada



The stuff is a bioflavonoid (not an enzyme) in grapefruit called
narangin.  It's an inhibitor of a particular P450 enzyme in liver which
deals with certain drugs like Plendyl, Seldane, Propulsid, and
cyclosporin.  Thus, it slows their metabolism and raises their levels
in the blood.

                                    Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Subject: Re: Grapefruit Juice and Medications
Date: Thu, 04 Dec 1997
Newsgroups: sci.chem,sci.med,sci.bio.misc

In <34859672.5717@erols.com> physical@erols.com writes:

>	Goddamm!  Steven B. Harris does it again!  Steve, you don't know all
>the details of science history (are we still friends??), but you sure
>know phytochemicals and blueberries!

   What details of science history did I screw up on?



>	I am curious as to what your sources are for this info, as I
would like >to do some (gulp) reading.<

    Science News, Medical Letter, abstracts on medline.  Search on
narangin and and I'm sure you'll get more than you want to know.


>	Also, furanocoumarins was a stretch.  I believe these are mostly
>in grasses/weeds, correct?  Cattle drop dead from them.

   Possibly you're thinking of dicoumarol, the stuff that
anticoagulates calves to death when they die of sweet clover disease?
Coumarin is innocuous, but dicoumarol, a condensation product of
coumarine and formaldehyde, acts like the drug coumadin/Warfarin.  (Of
course, that's the ultimate source of the drug-- scientists making
synthetic derivatives of coumarin).  Coumadin is a phenyl-coumarin, so
perhaps furanocoumarins are vitamin K antagonists of the same sort?

>	"Narangin" is an interesting name, reminds me of "naranja",
>which is spanish for orange.  Might this flavanoid be in most citrus?

    I'ts all the same Indo-European root.  The Sanskrit word for
orange, Naranj, is one of the oldest words known.  If you ask a Hindu
what that fruit is, you'll recognize what he says right off.  Our word,
and the Spanish, come from the Persian by way of the Latin.  To answer
your other question, oddly enough there isn't much narangin in oranges
(where it was discovered) as compared with grapefruit.  Yes, there is
some of the stuff in all citrus, but not enough in most citrus to have
a metabolic effect.  Grapefruit you need.   Or, I assume, Pomello.

> And would it not be more in the rind?

   The "albedo" which is the white cheesy coating under the rind,
actually, has most of the bioflavonoids.  But there enough narangin in
the juice for an effect, mainly because it's water soluable.  Flavonoid
aglycones like narangenin are found mostly in the albedo.



>	Lastly, is it possible for watermelon or its seeds to cause heart
>palpitations?  I think I have narrowed it down to the seeds (which I
>gather are entirely digestible), but I swear I am going to faint
>sometimes after a goodly serving!


   I don't know of any toxins in the seeds, but I haven't done a
toxline search, either.

                                     Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Subject: Re: Grapefruit Juice and Medications
Date: Thu, 04 Dec 1997
Newsgroups: sci.chem,sci.med,sci.bio.misc

In <663qkh$4rl$7@newsfep1.sprintmail.com> kurtullman@sprintmail.com
(Kurt Ullman) writes:

>In article <662vuj$b48@sjx-ixn10.ix.netcom.com>, sbharris@ix.netcom.com(Steven
>B. Harris) wrote:
>
>>The stuff is a bioflavonoid (not an enzyme) in grapefruit called
>>narangin.  It's an inhibitor of a particular P450 enzyme in liver which
>>deals with certain drugs like Plendyl, Seldane, Propulsid, and
>>cyclosporin.  Thus, it slows their metabolism and raises their levels
>>in the blood.
>
>        The other question then would be: How grapefruits a day would one have
>to eat to get to levels where it would be a problem?



    Why do you want to know?  If you take any of the cardiotoxic drugs
like seldane or propulsid you'd be a fool to eat any at all.  If you
want to save money on cyclosporin and dihydropyridone calcium channel
blockers, under a doctor's care, you'll want to drink enough grapefruit
juice to make sure you do the job, which is 8 oz a day of the 100%
stuff (not the drink).

                                     Steve Harris, M.D.

From: "Robert R. Fenichel" <ms671691@mindspring.com>
Newsgroups: sci.med.cardiology
Subject: Re: anti Grapefruit
Date: Sat, 13 Mar 1999 10:56:45 -0500

  Grapefruit juice (but NOT other common citrus juice) contains a
substance that inhibits a liver enzyme called CYP3A4, formerly called
cytochrome P450/3A4.  This enzyme is responsible for metabolism of a
large number of drugs, so the blood levels of those drugs rise, possibly
to toxic levels, when the enzyme is inhibited. The drugs affected are
     all of the dihydropyridine calcium-channel blockers (nifedipine,
felodipine, amlodipine, etc.)
     verapamil (but NOT diltiazem)
     simvastatin and lovastatin (but NOT the other statin
anti-cholesterol drugs)
     cisapride
     astemizole
     cyclosporine
and lots of others.  Grapefruit juice is not as potent an inhibitor of
CYP3A4 as some drugs (for example, ketoconazole or mibefradil), but it's
a more potent inhibitor than most.

  There are no good data as to how long it takes the body to recover its CYP3A4
capacity after inhibition with grapefruit juice.

ROCKYD wrote:

> http://heartinfo.org/science/grapefruit41698.htm
>
> http://pharminfo.com/pubs/msb/gfj_effect.html
>
> Stewart Rowe wrote:
>
> > MaxGip4517 (maxgip4517@aol.com) writes:
> > > I  am know as "anti-grapefruit" at cardiac re-hab because I constantly tell my
> > > fellow heart patients that they probably should not be eating grapefruit. I can
> > > not come up with the official reasion that I am telling them this, but it has
> > > something to do with changing the rate of uptake of some drugs. Where did I
> > > hear this, and why am I repeating it? Is it right to be concerned about eating
> > > grapefruit if one is taking heart medication?
> > > Thanks
> > > Max
> > > MAXGIPnospam4517@AOL.NOSPAM
> >
> > You need to determine whether those drugs you are using are among the
> > specific drugs which have been found to be affected. For example,
> > Cardizem (diltiazem) is NOT affected even though a number of other
> > calcium-channel blockers are. I believe that the antibiotic erythrosporin
> > causes the same effects.
> >
> > Some drugs need to be processed by certain liver enzymes to become
> > the active form. Grapefruit ties up the enzymes and reduces the effective
> > level of the drug in the system.  Other drugs are eliminated from
> > the system slowly using these same enzymes, so grapefruit delays
> > elimination resulting in a higher than intended dose, which could
> > be dangerous for some drugs.
> >
> > Medscape has a paper by Rodvold in their archives which reviews this.
> >
> > Stewart Rowe srowe@tso.cin.ix.net
> > 1

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med.nutrition,sci.med
Subject: Re: Question: Don't take MEDS with CITRUS
Date: 26 Sep 2005 15:12:58 -0700
Message-ID: <1127772778.767522.203330@f14g2000cwb.googlegroups.com>

fresh~horses@despammed.com wrote:
> theozz86@yahoo.com wrote:
> > Hi, I was wondering if anyone could help me with sumthing.
> >
> > Is it bad to drink orange juice in conjunction with medicine and
> > supplements???
> >
> > My parents tell me its bad for my stomach if I do that, but I think its
> > a load of crap.
>
>
>
> Your parents are right. I'm a parent. I'm right.
>
> Don't take your meds with any citrus; orange, grapefruit, pommelos
> (hybrids of grapefruit) etc. Not with the juice or the whole fruit.
>
> The Parents' Rule on Swilling Juice with Meds is this:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_
>
> Drug Saf. 2005;28(8):677-94.
> Undesirable effects of citrus juice on the pharmacokinetics of drugs:
> focus on recent studies.
>
> Saito M, Hirata-Koizumi M, Matsumoto M, Urano T, Hasegawa R.
>
>     Division of Medicinal Safety Science, National Institute of Health
> Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
> m-saito@nihs.go.jp
>
>     It is well known that intake of grapefruit juice affects the
> pharmacokinetics of various kinds of drugs. It has been reported that
> other citrus juices also interact with certain drugs. To re-evaluate
> citrus juice-drug interactions based on currently available evidence, a
> literature search was conducted for new and updated information since
> the grapefruit juice-drug interaction was last reviewed in 1998.
> MEDLINE (1998-October 2004) was accessed and more than 200 reports were
> found. The effects of grapefruit juice ingestion on the
> pharmacokinetics of orally administered drugs have been reported for 40
> drugs since the reviews published in 1998. Increases in either area
> under the concentration-time curve (AUC) or maximum plasma
> concentration (C(max)) were found with 34 of these, the major mechanism
> being considered to be inactivation of intestinal cytochrome P450 3A4,
> a so-called mechanism-based inhibition. Although recent reports point
> to the inhibitory effects of grapefruit juice on the function of
> P-glycoprotein, which transports substrates from enterocytes back into
> the lumen, the contribution to the bioavailability of drugs that are
> substrates of P-glycoprotein has not been established yet. Dramatic
> decreases in AUC and C(max) for two drugs in association with
> grapefruit juice ingestion has been reported and, in these cases,
> inhibitory effects on organic anion transporting polypeptide, which
> mediates absorption from the intestinal lumen to enterocytes, might be
> involved. Other citrus juices such as Seville (sour) orange juice and
> commonly ingested varieties of orange juice also showed significant
> effects on the AUC and C(max) of some drugs. Although the situation is
> complex and uncertainties remain, we recommend that patients avoid
> citrus juice intake while taking medications and that healthcare
> providers advise against citrus juice intake in this setting until any
> interactions with subject drugs can be clarified in clinical studies.
>
>     PMID: 16048354 [PubMed - in process]


Well, how about that?  The things you find out, if you look.

However, I'd bet that if you systematically examined every other class
of plant food-- maybe any food-- you'd also find some shocking
surprises on effects on biavailability of specific drugs. We usually
just close our eyes and ignore this stuff, unless it's an inhibitor
which leads to greatly INCREASED blood levels, as with the grapefruit
P450 interaction mentioned. For other drugs, people eating a given meal
probably just miss an occasional amount of drug and never notice.

I'll keep the juice-law in mind!

SBH